EP0630898B1 - Remede contre la thrombopenie - Google Patents

Remede contre la thrombopenie Download PDF

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Publication number
EP0630898B1
EP0630898B1 EP93919687A EP93919687A EP0630898B1 EP 0630898 B1 EP0630898 B1 EP 0630898B1 EP 93919687 A EP93919687 A EP 93919687A EP 93919687 A EP93919687 A EP 93919687A EP 0630898 B1 EP0630898 B1 EP 0630898B1
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Prior art keywords
compound
hydrogen
carbon atoms
mmol
chloroform
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EP0630898A1 (fr
EP0630898A4 (fr
Inventor
Tatsuya Tamaoki
Yukimasa Shiotsu
Chikara Murakata
Shiro Akinaga
Masami Okabe
Yutaka Saitoh
Junichi Watanabe
Takako Shiraki
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KH Neochem Co Ltd
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Kyowa Hakko Kogyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/044—Pyrrole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/06—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing nitrogen as ring hetero atoms

Definitions

  • the present invention relates to a therapeutic agent for thrombocytopenia and novel indolocarbazole derivatives.
  • Therapeutic agents for thrombocytopenia are expected to be useful for the treatment of the decrease in the number of blood platelets which is a side effect of chemotherapy for cancer and transplantation of bone marrow and for various diseases involving thrombocytopenia.
  • IL interleukin 6
  • IL 11 interleukin 11
  • Indolocarbazole derivatives are known to have inhibitory activity against a variety of protein kinase, including protein kinase C, antibacterial activity, and anti-tumor activity [Japanese Published Unexamined Patent Application No. 155284/87, Japanese Published Unexamined Patent Application No. 220196/87 (EP-A-238011), Japanese Published Unexamined Patent Application No. 295588/88, Japanese Published Unexamined Patent Application No. 295589/88, Japanese Published Unexamined Patent Application No. 168689/89 (EP-A-323171), WO 88-07045 (U.S.P. 4923986), WO 89-07105 (EP-A-383919)].
  • R 1 represents hydrogen, 1-6 carbon atoms alkyl, 1-7 carbon atoms alkanoyl, benzyl or amino
  • R 2 represents hydrogen, hydroxy, 1-6 carbon atoms alkoxy, 1-7 carbon atoms alkanoyl, halogen or the formula (i):
  • R 3 represents hydrogen, 1-7 carbon atoms alkanoyl, halogen, hydroxy or 1-6 carbon atoms alkoxy
  • one of W 1 and W 2 is hydrogen, and the other is hydrogen, hydroxy or 1-6 carbon atoms alkylthio, or W 1 and W 2 are combined together to represent oxygen
  • a 1 and A 2 are the same and are hydrogen, or A 1 and A 2 are combined together to represent the formula (ii): (wherein R 6 is hydrogen, benzyloxycarbonyl, 1-6 carbon atoms alkyl or 1-7 carbon atoms alkanoy
  • the therapeutic agent according to the present invention is effective in increasing the reduced number of blood platelets.
  • the alkyl means a straight-chain or branched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, and hexyl.
  • alkyl moiety of the alkoxy, alkoxycarbonyl and alkylthio has the same definition as the alkyl mentioned above.
  • the alkanoyl means an alkanoyl group having 1-7 carbon atoms, such as formyl, acetyl, propionyl, isopropionyl, butyryl, valeryl, pivaloyl, hexanoyl, and heptanoyl.
  • the pharmaceutically acceptable salts of Compound I include salts with inorganic acids such as hydrochloride, sulfate, and phosphate, and salts with organic acids such as acetate, maleate, fumarate, tartrate, citrate, lactate, aspartate, and glutamate.
  • n-Pr stands for -(CH 2 ) 2 CH 3
  • i-Pr stands for -CH(CH 3 ) 2
  • n-Bu stands for -(CH 2 ) 3 CH 3
  • n-Hex stands for -(CH 2 ) 5 CH 3
  • Bn stands for benzyl.
  • the present invention also provides indolocarbazole derivatives represented by the formulae (II) and (III) and pharmaceutically acceptable salts thereof. [In the formula,
  • Examples of the compounds represented by the general formula (II) include Compounds I-20, I-21, I-24, I-29, I-30, I-31, I-32, I-33, I-39, I-47, I-48, I-49, I-50 and I-51.
  • R 1a represents hexyl or benzyl
  • Y represents benzyl or tert-butyl
  • X represents I, Br or Cl
  • W 1 , W 2 , R 2 and R 3 have the same meanings as defined above.
  • Compound (A) is allowed to react with R 1a X in the presence of a base such as sodium hydride in an appropriate solvent such as dimethylformamide (DMF) to give Compound (EG).
  • a base such as sodium hydride
  • an appropriate solvent such as dimethylformamide (DMF)
  • Sodium hydride and R 1a X are used in amounts of 1 to 5 equivalents based on Compound (A). The reaction is carried out at -23 to 30°C and is completed in 1 to 8 hours.
  • Compound (EG) wherein Y is benzyl is subjected to deprotection in a hydrogen stream, in the presence of a catalyst such as 10% Pd/C or 10% Pd(OH) 2 /C, in an appropriate solvent such as DMF to give Compound (Ia).
  • a catalyst such as 10% Pd/C or 10% Pd(OH) 2 /C
  • an appropriate solvent such as DMF
  • the amount of the catalyst to be used is 0.1 to 2 times that of Compound (EG) by weight.
  • the reaction is carried out at 0 to 80°C and is completed in 1 to 8 hours.
  • R 6a represents hydrogen or C 1-5 lower alkyl; and R 1 , R 2 , R 3 , W 1 and W 2 have the same meanings as defined above.
  • Compound (N) is allowed to react with R 6a CHO in the presence of a reducing agent such as sodium cyanoborohydride in an appropriate solvent such as tetrahydrofuran (THF) to give Compound (Ib).
  • a reducing agent such as sodium cyanoborohydride
  • an appropriate solvent such as tetrahydrofuran (THF)
  • the reducing agent and R 6a CHO are used in amounts of 1 to 2 equivalents and 1 to 5 equivalents, respectively, based on Compound (N).
  • the reaction is carried out at 0 to 30°C and is completed in 1 to 5 hours.
  • R 2a represents Cl or Br; and R 1 , R 6 , W 1 and W 2 have the same meanings as defined above.
  • Compound (O) is allowed to react with a halogen or Compound (P) in an appropriate solvent such as chloroform to give Compound (Ic).
  • the halogen or Compound (P) is used in an amount of 0.8 to 1.5 equivalents based on Compound (O). The reaction is completed in 1 to 8 hours.
  • R 2b represents alkanoyl of 2-7 carbon atoms
  • R 3a represents hydrogen or R 2b
  • R 1 , W 1 and W 2 have the same meanings as defined above.
  • Compound (Q) is allowed to react with an alkanoyl chloride in the presence of an appropriate Lewis acid such as aluminum chloride in an appropriate solvent such as dichloromethane to give Compound (R) and Compound (Id).
  • the alkanoyl chloride and the Lewis acid are used in amounts of 1 to 8 equivalents based on Compound (Q).
  • the reaction is carried out at -10 to 30°C and is completed in 1 to 8 hours.
  • Compound (Id) may also be obtained by catalytic reduction of Compound (R) in the same manner as in the case of Compound (Ia).
  • R 3c represents hydrogen or formyl; and R 1 , W 1 and W 2 have the same meanings as defined above.
  • Compound (Q) is allowed to react with dichloromethyl methyl ether in the presence of a Lewis acid such as titanium tetrachloride in an appropriate solvent such as dichloromethane to give Compound (Ie).
  • a Lewis acid such as titanium tetrachloride
  • dichloromethane an appropriate solvent such as dichloromethane
  • Dichloromethyl methyl ether and Lewis acid are used in amounts of 1.5 to 3 equivalents based on Compound (Q). The reaction is carried out at -10 to 30°C and is completed in 1 to 5 hours.
  • R 2c represents lower alkyl; and X has the same meaning as defined above.
  • Compound (R-1) is allowed to react with acetic anhydride in the presence of a base such as 4-dimethylaminopyridine in an appropriate solvent such as THF to give Compound (R-2).
  • a base such as 4-dimethylaminopyridine
  • THF an appropriate solvent
  • 4-Dimethylaminopyridine and acetic anhydride are used in amounts of 1 to 8 equivalents and 5 to 20 equivalents, respectively, based on Compound (R-1). The reaction is carried out at 20 to 90°C and is completed in 5 to 15 hours.
  • Compound (R-2) is allowed to react with an oxidizing agent such as m-chloroperbenzoic acid in the presence of a base such as sodium bicarbonate in an appropriate solvent such as chloroform to give Compound (S).
  • a base such as sodium bicarbonate
  • m-chloroperbenzoic acid are used in amounts of 3 to 8 equivalents based on Compound (R-2). The reaction is carried out at 0 to 50°C and is completed in 5 hours to one day.
  • Compound (S) is treated with sodium methylate or the like in an appropriate solvent such as dichloromethane to give Compound (T).
  • Sodium methylate is used in an amount of 1 to 5 equivalents, and the reaction is completed in 5 to 30 minutes.
  • Compound (T) is allowed to react with R 2c X in the presence of a base such as sodium hydride in an appropriate solvent such as DMF to give Compound (U).
  • a base such as sodium hydride
  • R 2c X are used in amounts of 0.8 to 1.2 equivalents and 1 to 5 equivalents, respectively, based on Compound (T).
  • the reaction is carried out at -10 to 20°C and is completed in 1 to 5 hours.
  • Compound (V) is allowed to react with methoxymethyl chloride in the presence of a base such as sodium hydride in an appropriate solvent such as THF to give Compound (Ig).
  • a base such as sodium hydride in an appropriate solvent such as THF
  • Sodium hydride and methoxymethyl chloride are used in amounts of 1 to 1.5 equivalents based on Compound (V). The reaction is carried out at 0 to 30°C and is completed in 1 to 2 days.
  • R 1b represents lower alkyl
  • R 3b represents hydroxy or hydrogen
  • R 7 represents OR 3a or hydrogen
  • W 1 , W 2 , R 2b and R 3a have the same meanings as defined above.
  • Isolation and purification of the products in the above processes can be carried out using an appropriate combination of methods conventionally used in organic synthesis, for example, extraction, crystallization and various types of chromatography.
  • An eight-weeks-old BALB/c mouse was killed. Its femurs and cervical vertebrae were taken out, and both end sections thereof were cut off. Bone marrow cells were collected from the pieces cut off from the femurs and cervical vertebrae using a syringe containing IMDM (430-2200EA prepared by Gibco Co.), and then blown into a test tube. The test tube was allowed to stand for 5 minutes, and the supernatant was collected with a pipet.
  • IMDM 430-2200EA prepared by Gibco Co.
  • reaction mixture comprising the bone marrow cells (50,000 cells), bovine serum albumin (2%: A4508 made by Sigma Co.), transferrin (600 ⁇ /ml: 652202 made by Boehringer Mannheim Co.), IL-3 (100 U/ml), cholesterol (16 ⁇ g/ml: 036-0641 made by Wako Co.) and agar (0.6%: 0142-02 made by Difco Laboratories) were separately added the test compounds at various concentrations, and 1 ml each of the mixtures was put into a 35-mm dish (Lux Co.), followed by incubation under the conditions of 37°C, 5% CO 2 and a humidity of 95% or more for 7 days.
  • IL-3 alone was added to the bone marrow cells to prepare a control
  • a positive control was prepared by adding 200 U/ml IL-6 to the above-mentioned reaction mixture.
  • the agar was dried over a filter paper (1001-055 made by Whatman Co.) and then fixed with 2.5% glutaraldehyde, followed by acetylcholinesterase staining (ACHE staining).
  • the ACHE staining was carried out by the method described below.
  • ACHE staining To each sample was added a solution comprising 0.67 mg/ml acetylthiocholine iodide, 2.94 mg/ml sodium citrate, 7.5 mg/ml copper (II) sulfate and 1.65 mg/ml potassium ferricyanide, and the mixture was allowed to stand at room temperature in the dark for 4-6 hours.
  • a group of 4 or more megakaryocytes which were stained reddish brown was regarded as a colony, and the number of colonies per dish was calculated using a microscope. The results are shown in Table 2 as relative values to the control.
  • mice Male, 7-weeks-old were divided into 2 groups. To one group (control group) was administered a solvent (1% lactic acid, 4% aqueous solution of glucose) alone. On the other hand, the test group (Compound I-1-administered group) received 0.2 ml of a solution of Compound I-1 in the above solvent at a dose of 7.5 mg/kg via the caudal vein once a day for 5 days (Day 1 - Day 5).
  • a solvent 1% lactic acid, 4% aqueous solution of glucose
  • Compound I and pharmaceutically acceptable salts thereof can be used directly or in the form of various pharmaceutical compositions for the intended administration purpose depending on their pharmacological activity.
  • the pharmaceutical compositions according to the present invention can be prepared by uniformly mixing an effective amount of Compound I or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier.
  • the carrier may vary in form over a wide range depending on the type of the preparation desired for the administration.
  • These pharmaceutical compositions are desired to be in a unit dose form which is appropriate for oral or non-oral administration.
  • the forms for non-oral administration include ointment and injection.
  • Tablets can be prepared using, in a conventional manner, excipients such as lactose, glucose, sucrose, mannitol and methyl cellulose, disintegrating agents such as starch, sodium alginate, calcium carboxymethyl cellulose and crystalline cellulose, lubricants such as magnesium stearate and talc, binders such as gelatin, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose and methyl cellulose, surface active agents such as sucrose fatty acid ester and sorbitol fatty acid ester, etc. Tablets each containing 50-200 mg of an active ingredient are appropriate.
  • excipients such as lactose, glucose, sucrose, mannitol and methyl cellulose
  • disintegrating agents such as starch, sodium alginate, calcium carboxymethyl cellulose and crystalline cellulose
  • lubricants such as magnesium stearate and talc
  • binders such as gelatin, polyvinyl alcohol, polyvinylpyrroli
  • excipients such as lactose and sucrose, disintegrating agents such as starch, binders such as gelatin, etc. may be used in a conventional manner.
  • excipients such as lactose and mannitol, etc. may be used in a conventional manner.
  • Capsules can be prepared using, in a conventional manner, gelatin, water, sucrose, gum arabic, sorbitol, glycerine, crystalline cellulose, magnesium stearate, talc, etc.
  • Capsules each containing 50-200 mg of an active ingredient are appropriate.
  • saccharides such as sucrose, water, ethanol, and so on may be used in a conventional manner.
  • ointment bases such as vaseline, liquid paraffin, lanolin and macrogol, emulsifying agents such as sodium lauryl lactate, benzalkonium chloride, sorbitan mono-fatty acid ester, sodium carboxymethyl cellulose and gum arabic, etc. may be used in a conventional manner.
  • Injectable preparations can be prepared using, in a conventional manner, solvents such as water, physiological saline, vegetable oil (e.g., olive oil and peanut oil), ethyl oleate and propylene glycol, solubilizing agents such as sodium benzoate, sodium salicylate and urethane, isotonizing agents such as sodium chloride and glucose, preservatives such as phenol, cresol, p-hydroxybenzoic ester and chlorobutanol, antioxidants such as ascorbic acid and sodium pyrosulfite, etc.
  • solvents such as water, physiological saline, vegetable oil (e.g., olive oil and peanut oil), ethyl oleate and propylene glycol, solubilizing agents such as sodium benzoate, sodium salicylate and urethane, isotonizing agents such as sodium chloride and glucose, preservatives such as phenol, cresol, p-hydroxybenzoic ester and chlorobutanol, antioxidants
  • Compound I and pharmaceutically acceptable salts thereof may be administered orally or non-orally as an ointment or an injection.
  • the effective dose and the administration schedule vary depending on the mode of administration, the age, body weight and symptoms of the patient, etc. However, it is generally appropriate to administer them at a daily dose of 22.5-100 mg/kg in 1 to 4 parts.
  • Tablets were prepared in a conventional manner using 180 mg of Compound I-1, 90 mg of lactose, 40 mg of corn starch, 4 mg of polyvinyl alcohol, 28 mg of Avicel and 1 mg of magnesium stearate.
  • Tablets were prepared in a conventional manner using 180 mg of Compound I-22, 90 mg of lactose, 40 mg of corn starch, 4 mg of polyvinyl alcohol, 28 mg of Avicel and 1 mg of magnesium stearate.
  • Compound I-48 (2.0 g) was dissolved in 20 1 of ethanol, and the solution was subjected to pressure filtration through Millipore Filter (pore size: 0.22 ⁇ ) for sterilization. The resulting sterile filtrate was put into brown vials in 5.0 ml portions and then lyophilized in a conventional manner to obtain 0.5 mg/vial of lyophilized preparations.
  • Tablets were prepared in a conventional manner using 180 mg of Compound I-48, 90 mg of lactose, 40 mg of corn starch, 4 mg of polyvinyl alcohol, 28 mg of Avicel and 1 mg of magnesium stearate.
  • Compound (E) was obtained from 100 mg (0.16 mmol) of Compound (A-1) and 70 ⁇ l (0.48 mmol) of hexyl iodide by the same procedure as in the synthesis of Compound I-19 described in Reference Example 2 (yield: 60.6 mg, 55.4%).
  • Compound I-20 was obtained from 50 mg of Compound (E) and 50 mg of 10% Pd/C by the same procedure as in the synthesis of Compound I-19 described in Reference Example 2 (yield: 15 mg, 36%).
  • Compound (G) was obtained from 113.2 mg (0.2 mmol) of Compound (A-2) and 47.5 ⁇ l (0.4 mmol) of benzyl bromide by the same procedure as in the synthesis of Compound I-19 described in Reference Example 2 (yield: 40 mg, 31%).
  • therapeutic agents for thrombocytopenia which are useful as medicines.

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Abstract

Un remède contre la thrombopénie contient comme principe actif un dérivé indolocarbazole représenté par la formule générale (I), ou bien un sel pharmacologiquement acceptable de celui-ci, ainsi qu'un nouveau dérivé indolocarbazole.

Claims (4)

  1. Emploi d'un dérivé d'indolocarbazole, représenté par la formule générale (I) :
    Figure 00750001
    dans laquelle
    R1 représente un atome d'hydrogène ou un groupe alkyle de 1 à 6 atomes de carbone, alcanoyle de 1 à 7 atomes de carbone, benzyle ou amino ;
    R2 représente un atome d'hydrogène ou d'halogène, un groupe hydroxy, alcoxy de 1 à 6 atomes de carbone ou alcanoyle de 1 à 7 atomes de carbone, ou un groupe de formule (i) :
    Figure 00750002
    R3 représente un atome d'hydrogène ou d'halogène ou un groupe alcanoyle de 1 à 7 atomes de carbone, hydroxy ou alcoxy de 1 à 7 atomes de carbone ;
    l'un des symboles W1 et W2 représente un atome d'hydrogène et l'autre représente un atome d'hydrogène ou un groupe hydroxy ou alkylthio de 1 à 6 atomes de carbone, ou bien W1 et W2 représentent ensemble un atome d'oxygène ;
    et A1 et A2 sont identiques et représentent chacun un atome d'hydrogène, ou A1 et A2 représentent ensemble un groupe de formule (ii) :
    Figure 00750003
    (où R6 représente un atome d'hydrogène ou un groupe benzyloxycarbonyle, alkyle de 1 à 6 atomes de carbone ou alcanoyle de 1 à 7 atomes de carbone),
    ou un groupe de formule (iii) :
    Figure 00760001
    (où R4 représente un atome d'hydrogène ou un groupe alkyle de 1 à 6 atomes de carbone, méthoxyméthyle ou alcanoyle de 1 à 7 atomes de carbone, et R5 représente un atome d'hydrogène ou un groupe alcoxycarbonyle de 2 à 7 atomes de carbone),
    ou d'un sel d'un tel dérivé, admissible en pharmacie, pour la préparation d'un agent thérapeutique destiné au traitement de la thrombopénie.
  2. Dérivé d'indolocarbazole représenté par la formule générale (II) :
    Figure 00760002
    dans laquelle
    a) R1A représente un groupe hexyle et R2A, R3A et R6A représentent des atomes d'hydrogène ;
    b) R1A représente un groupe benzyle et R2A, R3A et R6A représentent des atomes d'hydrogène ;
    c) R1A représente un groupe méthyle, R2A et R3A représentent des atomes d'hydrogène et R6A représente un groupe alkyle de 1 à 6 atomes de carbone ;
    d) R1A représente un atome d'hydrogène ou un groupe alkyle de 1 à 6 atomes de carbone, R3A et R6A représentent des atomes d'hydrogène et R2A représente un atome d'halogène ou un groupe alcanoyle de 1 à 7 atomes de carbone ;
    e) R1A représente un atome d'hydrogène ou un groupe alkyle de 1 à 6 atomes de carbone, R6A représente un atome d'hydrogène et R2A et R3A représentent des groupes alcanoyle de 1 à 7 atomes de carbone ;
    f) R1A, R3A et R6A représentent des atomes d'hydrogène et R2A représente un groupe alcoxy de 1 à 6 atomes de carbone ; ou
    g) R1A représente un groupe alkyle de 1 à 6 atomes de carbone, R6A représente un atome d'hydrogène, R2A représente un groupe hydroxy et R3A représente un groupe hydroxy ou un atome d'hydrogène ;
    ou sel d'un tel dérivé, admissible en pharmacie.
  3. Dérivé d'indolocarbazole représenté par la formule générale suivante (III) :
    Figure 00770001
  4. Dérivé d'indolocarbazole conforme à la revendication 2 ou 3, destiné à être employé comme médicament.
EP93919687A 1992-09-21 1993-09-20 Remede contre la thrombopenie Expired - Lifetime EP0630898B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP25094192 1992-09-21
JP25094192 1992-09-21
JP250941/92 1992-09-21
PCT/JP1993/001346 WO1994006799A1 (fr) 1992-09-21 1993-09-20 Remede contre la thrombopenie

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Publication Number Publication Date
EP0630898A1 EP0630898A1 (fr) 1994-12-28
EP0630898A4 EP0630898A4 (fr) 1995-04-26
EP0630898B1 true EP0630898B1 (fr) 2001-11-28

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US (1) US5674867A (fr)
EP (1) EP0630898B1 (fr)
CA (1) CA2123895A1 (fr)
DE (2) DE69331228T4 (fr)
ES (1) ES2171416T3 (fr)
WO (1) WO1994006799A1 (fr)

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WO2013061305A1 (fr) 2011-10-28 2013-05-02 Novartis Ag Nouveaux dérivés de purine et utilisation de ceux-ci dans le traitement d'une maladie
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US5674867A (en) 1997-10-07
DE69331228D1 (en) 2002-01-10
DE69331228T4 (de) 2002-09-05
CA2123895A1 (fr) 1994-03-31
WO1994006799A1 (fr) 1994-03-31
ES2171416T3 (es) 2002-09-16
DE69331228T2 (de) 2002-05-23
EP0630898A1 (fr) 1994-12-28
EP0630898A4 (fr) 1995-04-26

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